A growing body of literature suggests that certain ion channels participate in fundamental aspects of a cells' biology that are unrelated to electrical signaling. Hence such channels are particularly relevant to non-excitable cells such as glial cells. In this proposal we are examining the role of Ca2+-activated K+ channels (KCa), a super-family of ion channels that have the unique ability to translate changes in intracellular Ca2+ to changes in K+ conductance and resting membrane potential. Ca2+ signaling appears to be particularly important in glial cells where propagating waves of activity can be observed in vitro and in vivo under both physiological conditions and in the context of disease and injury. We suggest that KCa channels are a downstream target of [unreadable] Ca2+ waves but also respond to growth factors and cytokines that trigger Ca2+ signals. We suggest in this proposal that KCa channels are of particular importance in glial cells: We hypothesize that activation of KCa channels is essential in the coordinated migration of glial cells during brain development, in malignancy and following injury. In this context, KCa channels participate in dynamic shape changes of the glial "invadipodia" but also play an important role in regulating programmed cells death (apoptosis). We further hypothesize that the function of KCa channels is most pronounced in glial populations that are still migratory and/or proliferative. Upon differentiation these channels are down regulated and replaced by Kir channels that aid in K+ homeostasis in the brain. However, KCa expression and function can be re-acquired in glial cells following acute injury (gliosis) and in disease states in which glial migration is prominent. The latter includes glial derived tumors that invade diffusely into normal brain. [unreadable] [unreadable] [unreadable]